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Timing Is Everything: The Pendulum Swings On

Chassard, Dominique M.D., Ph.D.*; Allaouchiche, Bernard M.D., Ph.D.; Boselli, Emmanuel M.D.

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IN his Introduction to Experimental Medicine in 1865, Claude Bernard noted that the physical state and chemical composition of the internal environment remains essentially constant. This idea was taken further by W. B. Cannon, who introduced the word homeostasis. Homeostasis is the maintenance of constant conditions in a biologic system by means of automatic mechanisms that counteract influences on disequilibrium.
On the other hand, chronobiology is a field of biology that examines time-related phenomena in living organisms. One century before Claude Bernard’s work, Jean Jacques d’Ortous de Mairan, a French astronomer, performed the first known experiment on biologic rhythms. He investigated the behavior of heliotrope, a plant with leaves that open during the day and close at night. He found that the leaves continued to open and close even when lighting levels were constant. This indicated that the force driving the plant’s rhythms was internally generated. The first observations of circadian rhythms in humans were made in 1866, when William Ogle noted that fluctuations in body temperature varied in synchrony with day and night.
These biologic rhythms have been observed in cells, tissues, organs, and human beings. At a given moment, a disruption in an organism is maintained at a certain value by a cascade of reactions. However, during a fixed period, the levels of biologic values are not constant, with variations of up to 50% sometimes observed. Without being opposed, homeostasis and biologic rhythms are in fact complementary and enable physiologic functions to adapt to an external environment.
The most important rhythm in chronobiology is circadian rhythm, which refers to the 24-h daily biologic cycle. However, many other important cycles are also studied, including ultradian (a cycle that is shorter than 1 day) and infradian rhythms (a cycle that may last weeks, months, or seasons). Circadian rhythms have been reported in heart rate, blood pressure, temperature, plasma concentrations of hormones and electrolytes, functions of the kidneys, the lung, the gastrointestinal tract, and the liver. The onset and symptoms of various diseases such as asthma and coronary ischemia are also not constant and exhibit temporal changes.1
Temporal change of pain has been found in patients with migraine, arthritis, and biliary colic pain.2 Variability in pain perception and sensitivity to analgesic therapy have long been noted.3 A 15–40% day–night difference for morphine consumption was noted in patients undergoing surgery.4 In surgical patients, the need for fentanyl was 30% less in a group of patients undergoing elective cholecystectomy performed earlier in the morning as compared with a late group. Numerous studies reported that the duration of action of local anesthetics exhibited temporal changes with a maximal analgesic effect during afternoon.5
We have previously shown that 10 μg intrathecal sufentanil for early labor analgesia exhibited a 30% variation in duration over the course of the day, with the shortest duration of analgesia at midnight (78 min) and the longest at noon (128 min).6
A study by Pan et al.7 in this issue of Anesthesiology continues the series of studies demonstrating that the duration of action of anesthetic agents is sensitive to the time of day, although analgesic requirements during the full 24-h period were not documented. The authors found a 27% reduction of spinal fentanyl in its duration of action in the early night period (8 pm to 2 am: 69 ± 5.0 min), compared with daytime (12 noon to 6 pm: 92 ± 6.0 min). The possibility that patient perception of labor pain differs throughout the day was advocated but not found in the studies of Debon et al.6 and Pan et al. Therefore, variation in the production of pain mediators or temporal change in opioid receptor affinity/receptor number during the 24-h period could participate in circadian changes observed in these clinical studies.
It has been also shown that biologic rhythms influence the pharmacology of anesthetic agents such as local anesthetics, hypnotics, and muscle relaxants.8 The real question is whether these circadian effects are of actual clinical importance in anesthesia and, if so, when and in which patients. Possibly, several domains of our practice of anesthesia or intensive care could be affected by chronobiology.
Many drugs used to treat critical care patients show temporal change. Studies have demonstrated that the pharmacokinetics of aminosid and certain antibiotics are altered by the time of day in critical care patients.9 Therefore, the right treatment given at the wrong time can be ineffective or create a crisis of escalating toxicity. Conversely, even a weak treatment, if given at the right moment, could prove surprisingly effective. However, although the clinical benefits of taking into account the time of day that a medication is administered have been clearly demonstrated in asthmatic and cancer patients, they have yet to be demonstrated in intensive care unit patients, and studies are required in the intensive care unit setting.
The implication of chronobiology in the practice of clinical anesthesia is probably of less importance except for the treatment of postoperative pain. Nonsteroidal antiinflammatory drugs, opioids, and α2 agonists are widely prescribed to cure postoperative pain.10 Many reports have shown that these drugs have a circadian component. The use of patient-controlled analgesia makes it possible to adapt to temporal variations of pain on nyctemeral rhythm, and for many of us, this method of administration represents a fortuitous introduction of the notion of chronobiology in anesthesia. The work of Pan et al. further encourages us to use self-controlled means of administration for obstetric analgesia or for postoperative pain relief.
On the other hand, it is difficult to foresee the overall influence of circadian effects on general anesthesia. We use several drugs to anesthetize a patient, and each drug has a particular chronobiologic profile that is not necessarily in tune with the others. It is therefore difficult to predict the overall effect of circadian changes on the course of anesthesia. One can consider that in the future, only the use of a monitor to detect the depth of anesthesia will make it possible to integrate the notion of chronobiology.
Finally, the domain in our specialty that is the most concerned with chronobiology is without a doubt that of clinical and experimental research.11 Much research has been done to understand how patient characteristics such as sex, age, weight, and recently, genetics relate to the pharmacokinetics and pharmacodynamics of anesthetic agents. Chronobiology should be considered as any other variable in pharmacokinetic studies of drugs used in the practice of anesthesia. It would be of interest to verify the impact of biorhythms on the pharmacokinetic models currently proposed in anesthesia.
Between the study that Munson et al.12 published in 1970 and that of Pan et al.7 in 2005, few clinical or experimental studies on chronobiology were published in the principal anesthesiology journals, whereas many studies have been published in the journals of other specialities. When one notes the marked differences observed in the studies by Pan et al. and Debon et al. (30% difference), one wonders whether most of the previously published studies should not be reevaluated. Considering that there are many other possible confounding factors in every study that can affect the conclusion, this recommendation must nevertheless be qualified without being excluded.
To conclude, the impact of time of the day remains relatively unknown in studies devoted to anesthesia. Although its current impact on the routine of anesthesia is minimal, it is likely that chronobiology will provide major contributions to the pharmacology of anesthetic agents currently used for anesthesia. The value of the studies by Pan et al. and Debon et al. is to emphasize that this impact is important and must not be ignored in future clinical or experimental research.
Dominique Chassard, M.D., Ph.D.*
Bernard Allaouchiche, M.D., Ph.D.
Emmanuel Boselli, M.D.
* Hotel-Dieu Hospital, Lyon, France.
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7. Pan PH, Lee S, Harris L: Chronobiology of subarachnoid fentanyl for labor analgesia. Anesthesiology 2005; 103:595–9

8. Debon R, Chassard D, Duflo F, Boselli E, Bryssine B, Allouachiche B: Chronobiology of epidural ropivacaine. Anesthesiology 2002; 96:542–5

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10. Morris RW, Lutsch EF: Susceptibility to morphine-induced analgesia in mice. Nature 1967; 216:494–5

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